This is a competing supplemental application in response to the Enabling RPGs to Leverage NCRR Center and Center-like Programs. The proposal is made based on our recent data suggesting a role of immune signaling pathways in snail immune defenses. This proposed study extends the scope of my current three-year R01 grant (NIAID, #AI067686). Understanding the fundamental mechanisms of internal defense in the snail Biomphalaria glabrata may lead to new methods for blocking the transmission of schistosomiasis, a snail-borne disease that affects 200 million people worldwide. Immune signaling pathways are evolutionarily conserved and believed to control most immune-related gene expression. Transcription factors are the key molecules regulating a given pathway. The immune signaling pathways TLR (Toll-like receptor), Imd (Immune deficiency), and Jak (Janus kinas)/STAT (signal transducer and activator of transcription) regulated by nuclear factor-kappa B (NF-?B) and STAT transcription factors have been shown to play the central role in humoral and cellular immune responses. In spite of the enormous amount of data accumulated in a wide phylogenetic range of animals, nothing is known about the existence and function of these immune signaling pathways in B. glabrata. We have identified two NF-?Bs (BgRel and BgRelish) and two STATs (BgSTAT1 and 2) from B. glabrata and examined their expression. Based on our preliminary data, we hypothesize that TLR, Imd, and Jak/STAT pathways are conserved in B. glabrata in terms of functionality. To test our hypothesis, we propose to investigate whether TLR, Imd, and Jak/STAT signaling pathways are activated in snails after exposure to S. mansoni. The outcome of this study may open a new area in the studies of snail immune signal transduction, which should improve our understanding of snail immunity and ultimately benefit the long-term goal of schistosomiasis control. PUBLIC HEALTH RELEVANCE: This proposed study will help us in better understanding the fundamental mechanisms of the internal defenses of the snail Biomphalaria glabrata, the intermediate host of human blood fluke Schistosoma mansoni. This may lead to new methods for blocking the transmission of Schistosomiasis, a snail-borne disease that affects 200 million people worldwide.